The present invention relates to a novel class of organic molecules capable of inhibiting the enzyme C-proteinase, pharmaceutical compositions comprising the C-proteinase inhibitory compounds and methods of using the compounds and compositions to regulate, modulate and/or inhibit collagen production and/or maturation as a therapeutic approach towards the treatment or prevention of myriad diseases related to, or associated with, unregulated collagen production.
Collagen Structure. At present, nineteen different types of collagens have been identified. These collagens, which include fibrillar collagen types I, II and III, are synthesized as procollagen precursor molecules which contain peptide extensions at both their amino- and carboxy-termini. These peptide extensions, referred to as xe2x80x9cpro-regions,xe2x80x9d are designated as N- and C-propeptides, respectively. The pro-regions are typically cleaved upon secretion of the procollagen triple helical precursor molecule from the cell to yield a mature triple helical collagen molecule. Upon cleavage, the xe2x80x9cmaturexe2x80x9d collagen molecule is capable of association, for example, into highly structured collagen fibers. See e.g., Fessler and Fessler, 1978, Annu. Rev. Biochem. 47:129-162; Bornstein and Traub, 1979, in: The Proteins (eds. Neurath, H. and Hill, R. H.), Academic Press, New York, pp. 412-632; Kivirikko et al., 1984, in: Extracellular Matrix Biochemistry (eds. Piez, K. A. and Reddi, A. H.), Elsevier Science Publishing Co., Inc., New York, pp. 83-118; Prockop and Kivirikko, 1984, N. Engl. J. Med. 311:376-383; Kuhn, 1987, in: Structure and Function of Collagen Types (eds. Mayne, R. and Burgeson, R. E.), Academic Press, Inc., Orlando, Fla., pp. 1-42.
Diseases Associated With The Abnormal Production of Collagen. A variety of critical diseases have been linked to inappropriate or unregulated collagen production and/or maturation. These diseases include pathological fibrosis or scarring (including endocardial sclerosis), idiopathic interstitial fibrosis, interstitial pulmonary fibrosis, perimuscular fibrosis, Symmers"" fibrosis, pericentral fibrosis, hepatitis, dermatofibroma, billary cirrhosis, alcoholic cirrhosis, acute pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, kidney fibrosis/glomerulonephritis, kidney fibrosis/diabetic nephropathy, scleroderma/systemic, scleroderma/local, keloids, hypertrophic scars, severe joint adhesions/arthritis, myelofibrosis, corneal scarring, cystic fibrosis, muscular dystrophy (duchenne""s), cardiac fibrosis, muscular fibrosis/retinal separation, esophageal stricture and payronles disease. Further fibrotic disorders may be induced or initiated by surgery, including scar revision/plastic surgeries, glaucoma, cataract fibrosis, corneal scarring, joint adhesions, graft vs. host disease, tendon surgery, nerve entrapment, dupuytren""s contracture, OB/GYN adhesions/fibrosis, pelvic adhesions, peridural fibrosis, restenosis. One strategy for the treatment of these diseases is to inhibit the pathological overproduction of collagen. Thus, identification and isolation of molecules which control, inhibit and/or modulate the production of collagen are of major medical interest.
Relationship Between Collagen Formation and C-Proteinase. Recent evidence suggests that C-proteinase is the essential key enzyme that catalyzes the cleavage of the C-propeptide of, for example, fibrillar collagens, including type I, type II, and type III collagen. See e.g. Prockep et al., 1998, Matrix Biol. 16:399-408; Lee et al., 1997, J. Biol. Chem. 272:19059-19066; Suzuk et al., 1996, Development 122:3587-3595.
C-proteinase was first observed in the culture media of human and mouse fibroblasts (Goldberg et al., 1975, Cell 4:45-50; Kessler and Goldberg, 1978, Anal. Biochem. 86:463-469), and chick tendon fibroblasts (Duskin et al., 1978, Arch. Biochem. Biophys. 185:326-332; Leung et al., 1979, J. Biol. Chem. 254:224-232). An acidic proteinase which removes the C-terminal propeptides from type I procollagen has also been identified. Davidson et al., 1979, Eur. J. Biochem. 100:551.
A partially purified protein having C-proteinase activity was obtained from chick calvaria in 1982. Njieha et al., 1982, Biochemistry 23:757-764. In 1985, chicken C-proteinase was isolated, purified and characterized from conditioned media of chick embryo tendons. Hojima et al., 1985, J. Biol. Chem. 260:15996-16003. Murine C-proteinase has been subsequently purified from media of cultured mouse fibroblasts. Kessler et al., 1986, Collagen Relat. Res. 6:249-266; Kessler and Adar, 1989, Eur. J. Biochem. 186:115-121. Finally, the cDNA encoding human C-proteinase has been identified (see, e.g., Takahara et al., 1994, J. Biol. Chem. 269:26280-26285; Li et al., 1996, Proc. Natl. Acad. Sci. USA 93:5127-5130; Kessler et al., 1996, Science 271:360-362.
C-Proteinase Inhibitors. Experiments conducted with purified forms of chick and mouse C-proteinases indicate that C-proteinase is instrumental in the formation of functional collagen fibers. Fertala et al., 1994, J. Biol. Chem. 269:11584. As a consequence of its critical role in collagen production and maturation, scientists have sought to identify compounds that inhibit C-proteinase. See e.g., Hojima et al., supra. Compounds identified to date include metal chelators (e.g., EDTA, phenanthroline, EGTA, basic amino acids (e.g., lysine and arginine), peptides (e.g., chymostatin, pepstatin A, and concanavalin A), proteins (e.g., xcex12-macroglobulin, ovostatin, and fetal bovine serum), metals ions (e.g., Zn2+, Cu2+, and Cd2+), reducing agents (e.g., dithiothreitol), detergents (e.g., sodium dodecyl sulfate (SDS)) and certain salts and buffers (e.g., phosphate, ammonium sulfate, sodium chloride and tris hydrochloride). In contrast, microbial inhibitors such as leupeptin, phosphoramidon, antipain, bestatin, elastinal, and amastatin are considered to have weak or no effect on the activity of C-proteinase. For references discussing the various C-proteinase inhibitors identified to date, see Leung et al., supra; Ryhxc3xa4nen et al., 1982, Arch. Biochem. Biophys. 215:230-236; WO97/05865; and the references cited therein.
Matrix Metalloproteinase Hydroxamic Acid Inhibitors
C-proteinase belongs to the matrix metalloproteinase (MMP) superfamily of zinc endopeptidases which are involved in tissue remodeling. Members of the MMP family include MMP-1 (human collagenase), MMP-2 (gelatinase), and MMP-9 (human gelatinase B). See e.g. WO98/34918; Krumme et al., 1998, FEBS Lett. 436:209-212. The MMPs are characterized by an active site zinc ion that plays an essential role in the enzymatic activity of MMPs. Rational drug discovery efforts, involving the inhibition of MMPs, have focused on inhibitor classes that contain a functional group that can coordinate the zinc ion and thereby inactivate the target MMP. See e.g. Krumme et al., supra. One such inhibitor class are hydroxamic acids. As revealed by the x-ray crystal structure determination of hydroxamic acid:MMP cocrystals, the hydroxamic acid coordinates the active site zinc in a bidentate manner via the hydroxyl and carbonyl oxygens of the hydroxamic group. See Grams et al., 1995, Biochem. 34:14012-14020; Bode et al., 1994, EMBO J., 13:1263-1269. Despite their potent affinity as zinc coordinators, hydroxamic acids demonstrate a considerable degree of specificity within the MMP family. Thus a potent inhibitor of MMP-1 (human collagenase) may have only minimal potency against another MMP such as C-proteinase. Thus the development of potent hydroxamic acid inhibitors against a particular MMP requires considerable research effort and experimentation.
Development of Compounds to Inhibit C-Proteinase Activity. In view of its essential role in the formation and maturation of collagen, C-proteinase provides an ideal therapeutic target towards the treatment or prevention of disorders related to, or associated with, unregulated collagen production or maturation. However, none of the C-proteinase inhibitors identified to date have proven to be clinically effective therapeutics for the treatment of collagen-related diseases. Accordingly, there remains a need in the art for compounds that are specific and potent inhibitors of C-proteinase, especially C-proteinase inhibitory compounds which provide clinically relevant benefits in the treatment or prevention of diseases associated with unregulated collagen production and/or maturation.
In one aspect, the present invention provides a novel class of organic molecules that are potent and/or selective inhibitors of C-proteinase. As a consequence of this activity, the compounds of the invention are capable of modulating, regulating or inhibiting collagen production or maturation by affecting C-proteinase activity.
The compounds of the invention are generally N-substituted arylsulfonylamino hydroxamic acids. In one embodiment, the compounds of the invention are N-aryl substituted arylsulfonylamino hydroxamic acids having the structural formula (I): 
or pharmaceutically acceptable salts thereof, wherein:
a is an integer from 1 to 4;
b is an integer from 0 to 4;
c is an integer from 0 to 4;
Ar1 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y1, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y1;
Ar2 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y2, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y2;
each Y1 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group; and
each Y2 is independently selected from the group consisting of a functional group having an acidic hydrogen, a functional group capable of participating in a hydrogen bond, a polar functional group, an electron-withdrawing functional group, an electron-donating functional group, and a lipophilic functional group,
with the provisos that:
(i) when a and b are each one, c is zero and Ar2 is 4xe2x80x2-methoxyphenyl, then Ar1 is other than phenyl, 4xe2x80x2-flourophenyl, 4xe2x80x2-chlorophenyl, 4xe2x80x2-trifluoromethylphenyl or 4xe2x80x2-methoxyphenyl; (ii) when a and b are each one, c is zero and Ar2 is phenyl, then Ar1 is other than 4xe2x80x2-chlorophenyl;
(iii) when a is two, b and c are each zero and Ar1 is phenyl, then Ar2 is other than 4xe2x80x2-chlorophenyl or 4xe2x80x2-bromophenyl; and
(iv) when a and b are each one, c is zero then Ar1 is other than carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, (N-aryl-lower alkylpiperazino)-lower alkyl
wherein, in proviso (iv), aryl represents monocyclic or bicyclic aryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclic aryl and heterocyclic aryl represents monocyclic or bicyclic heterocyclic aryl.
In another embodiment, the compounds of the invention are N-aryl substituted arylsulfonylamino hydroxamic acids having the structural formula (II): 
or pharmaceutically acceptable salts thereof, wherein:
d is an integer from 1 to 4;
e is an integer from 0 to 4;
f is an integer from 0 to 4;
Ar3 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y3, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y3;
Ar4 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y4, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y4;
each Y3 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -halogen, methyl, xe2x80x94SO2NH2 and trihalomethyl;
each Y4 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, and xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl; and
each Rxe2x80x3 is independently selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, halogen or trihalomethyl groups,
with the provisos that:
(i) when d and e are each one, f is zero and Ar4 is 4xe2x80x2-methoxyphenyl, then Ar3 is other than phenyl, 4xe2x80x2-fluorophenyl, 4xe2x80x2-chlorophenyl, 4xe2x80x2-trifluoromethylphenyl or 4xe2x80x2-methoxyphenyl;
(ii) when d and e are each one, f is zero and Ar4 is phenyl, then Ar3 is other than 4xe2x80x2-chlorophenyl;
(iii) when d is two, d and e are each zero and Ar3 is phenyl, then Ar4 is other than 4xe2x80x2-chlorophenyl or 4xe2x80x2-bromophenyl; and
(iv) when d and e are each one, f is zero then Ar3 is other than carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, (N-aryl-lower alkylpiperazino)-lower alkyl
wherein, in proviso (iv), aryl represents monocyclic or bicyclic aryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclic aryl and heterocyclic aryl represents monocyclic or bicyclic heterocyclic aryl.
In another embodiment, the compounds of the invention are N-cycloalkyl or N-heterocycloalkyl substituted arylsulfonylamino hydroxamic acids having the structural formula (III): 
or pharmaceutically acceptable salts thereof, wherein:
g is an integer from 1 to 4;
h is an integer from 0 to 4;
i is an integer from 0 to 4;
Z is selected from the group consisting of (C3-C10) cycloalkyl, (C3-C10) cycloalkyl independently substituted with one or more Y5, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkyl independently substituted with one or more Y5;
Ar6 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y6, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y6;
each Y5 is independently selected from the group consisting of a lipophilic functional group, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl;
each Y6 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, and xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2; and
Rxe2x80x2 and Rxe2x80x3 are as previously defined for structure (II),
with the proviso that when g and h is 1, i is 0, and Ar6 is phenyl, then Z is other than C3-C7-cycloalkyl, C3-C7-cycloalkyl-lower alkyl, N-lower alkyl-piperazino-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl.
In another embodiment, the compounds of the invention are Nxe2x80x2 substituted urea-arylsulfonylamino hydroxamic acids having the structural formula (IV): 
or pharmaceutically acceptable salts thereof, wherein:
j is an integer from 1 to 4;
k is an integer from 0 to 4;
Ar7 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y7, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y7;
R18 and R19 are each independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C10) cycloalkyl, (C5-C20) aryl, (C5-C20) substituted aryl, (C6-C26) alkaryl, (C6-C26) substituted alkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 membered substituted alk-heteroaryl; and
each Y7 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
In another embodiment, the compounds of the present invention are substituted urea compounds having the structural formula (V): 
or pharmaceutically acceptable salts thereof, wherein:
l is an integer from 1 to 4;
m is an integer from 0 to 4;
Ar8 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y8, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y8;
R20 is selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C10) cycloalkyl, (C5-C20) aryl, (C5-C20) substituted aryl, (C6-C26) alkaryl, (C6-C26) substituted alkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 membered substituted alk-heteroaryl;
R21 is independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl; and
each Y8 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
In another embodiment, the compounds of the present invention are benzoyl substituted hydroxamic acids having the structural formula (VI): 
or pharmaceutically acceptable salts thereof, wherein:
n is an integer from 1 to 4;
o is an integer from 0 to 4;
Ar9 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y9, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y9; and
each R25, R26, R27, R28, R29 and Y9 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
In a final embodiment, the compounds of the invention are benzylsulfonyl substituted hydroxamic acids having the structural formula (VII): 
or pharmaceutically acceptable salts thereof, wherein:
p is an integer from 1 to 4;
q is an integer from 0 to 4;
Ar10 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y8, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y9; and
each R33, R34, R35, R36, R37 and Y10 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
In another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the above-described compounds and a pharmaceutically acceptable carrier, diluent or excipient. Such a composition can be used in the methods of the invention to inhibit, regulate or modulate the production or maturation of collagen by inhibiting C-proteinase activity and to treat or prevent a variety of collagen-related disorders.
In yet another aspect, the invention provides methods of inhibiting C-proteinase activity. The method involves contacting the enzyme C-proteinase, or an active fragment or derivative thereof, with an amount of a compound or composition according to the invention effective to block collagen production. Methods of inhibiting C-proteinase in vivo can be used to inhibit, regulate or modulate collagen production or maturation as a therapeutic approach towards the treatment or prevention of disorders related to, or associated with, unregulated collagen production or maturation.
In a final aspect, the present invention provides methods for the treatment or prevention of disorders related to, or associated with, inappropriate or unregulated collagen production or maturation. The method involves administering to an animal subject, including a human, an amount of a compound according to the invention, or a pharmaceutical composition thereof, effective to treat or prevent the particular collagen-related disorder.
Disorders which can be treated or prevented according to the methods of the invention include, but are not limited to, rheumatoid arthritis, scleroderma, pathological fibrosis or scarring.
As used herein, the following terms shall have the following meanings:
xe2x80x9cC-proteinase:xe2x80x9d refers to an enzyme capable of processing collagen molecules, derivatives or fragments of collagen molecules or precursors of collagen molecules, collagen derivatives or collagen fragments by cleaving the amino acid sequence xe2x80x94Ala⇓Asp-Aspxe2x80x94, xe2x80x94Gly⇓Asp-Gluxe2x80x94 and/or xe2x80x94Ala⇓Asp-Glnxe2x80x94 at the position marked with xe2x80x9c⇓xe2x80x9d. The term xe2x80x9cC-proteinasexe2x80x9d includes human C-proteinase as well as derivatives, analogs, fragments and variants thereof capable of processing collagen molecules as described above.
xe2x80x9cAlkyl:xe2x80x9d refers to a saturated branched, straight chain or cyclic hydrocarbon radical. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl, hexyl, cyclohexyl and the like. In preferred embodiments, the alkyl groups are (C1-C8) alkyl, more preferably (C1-C6) alkyl and most preferably (C1-C3) alkyl.
xe2x80x9cAlkenyl:xe2x80x9d refers to an unsaturated branched, straight chain or cyclic hydrocarbon radical having at least one carbon-carbon double bond. The radical may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl, vinylidene, propenyl, propylidene, isopropenyl, isopropylidene, butenyl, butenylidene, isobutenyl, tert-butenyl, cyclobutenyl, pentenyl, isopentenyl, cyclopentenyl, hexenyl, cyclohexenyl and the like. In preferred embodiments, the alkenyl group is (C2-C8) alkenyl, more preferably (C2-C6) alkenyl and most preferably (C2-C3) alkenyl.
xe2x80x9cAlkynyl:xe2x80x9d refers to an unsaturated branched, straight chain or cyclic hydrocarbon radical having at least one carbon-carbon triple bond. Typical alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl and the like. In preferred embodiments, the alkynyl group is (C2-C8) alkynyl, more preferably (C2-C6) and most preferably (C2-C3) alkynyl.
xe2x80x9cCycloalkyl:xe2x80x9d refers to a cyclic or polycyclic saturated or unsaturated hydrocarbon radical. Typical cycloalkyl groups include, but are not limited to, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl and higher cycloalkyls, adamantyl, cubanyl, prismanyl and higher polycylicalkyls, etc. In preferred embodiments, the cycloalkyl is (C3-C10) cycloalkyl. Particularly preferred cycloalkyls are cyclohexanyl and adamantyl.
xe2x80x9cHeterocycloalkyl:xe2x80x9d refers to a cycloalkyl moiety wherein one of the ring carbon atoms is replaced with another atom such as N, P, O, S, As, Ge, Se, Si, Te, etc. Typical heterocycloalkyls include, but are not limited to, imidazolidyl, piperazyl, piperidyl, pyrazolidyl, pyrrolidyl, quinuclidyl, etc. In preferred embodiments, the cycloheteroalkyl is 5-10 membered. Particularly preferred cycloheteroalkyls are morpholino, tetrahydrofuryl, and pyrrolidyl.
xe2x80x9cSubstituted Cycloalkyl or Cylcoheteroalkyl:xe2x80x9d refers to a cycloalkyl or cycloheteroalkyl radical wherein one or more hydrogen atoms are each independently replaced with another substituent. Typical substituents include, but are not limited to, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NRR)xe2x95x90NR, xe2x80x94C(O)NROR, xe2x80x94C(NRR)xe2x95x90NOR, xe2x80x94NRxe2x80x94C(O)R, -tetrazol-5-yl, xe2x80x94NRxe2x80x94SO2xe2x80x94R, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, xe2x80x94NRxe2x80x94C(O)xe2x80x94OR, -halogen and -trihalomethyl where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl, and 6-26 membered alk-heteroaryl as defined herein.
xe2x80x9cAryl:xe2x80x9d refers to an unsaturated cyclic hydrocarbon radical having a conjugated n electron system. Typical aryl groups include, but are not limited to, penta-2,4-dienyl, phenyl, naphthyl, aceanthrylyl, acenaphthyl, anthracyl, azulenyl, chrysenyl, indacenyl, indanyl, ovalenyl, perylenyl, phenanthrenyl, phenalenyl, picenyl, pyrenyl, pyranthrenyl, rubicenyl and the like. In preferred embodiments, the aryl group is (C5-C20) aryl, more preferably (C5-C10) aryl and most preferably phenyl.
xe2x80x9cSubstituted Aryl:xe2x80x9d refers to an aryl radical wherein one or more hydrogen atoms are each independently replaced with another substituent. Typical substituents include, but are not limited to, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NRR)xe2x95x90NR, xe2x80x94C(O)NROR, xe2x80x94C(NRR)xe2x95x90NOR, xe2x80x94NRxe2x80x94C(O)R, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, xe2x80x94NRxe2x80x94C(O)xe2x80x94OR, xe2x80x94NRxe2x80x94SO2xe2x80x94R, -tetrazol-5-yl, -halogen and -trihalomethyl where each R is independently xe2x80x94H(C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, heteroaryl and alk-heteroaryl as defined herein.
xe2x80x9cAlkaryl:xe2x80x9d refers to a straight-chain (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl group wherein one of the hydrogen atoms bonded to the terminal carbon is replaced with an (C5-C20) aryl moiety. Alkaryl also refers to a branched-chain alkyl, alkenyl or alkynyl group wherein one of the hydrogen atoms bonded to a terminal carbon is replaced with an aryl moiety. Typical alkaryl groups include, but are not limited to, benzyl, benzylidene, benzylidyne, benzenobenzyl, naphthalenobenzyl and the like. In preferred embodiments, the alkaryl group is (C6-C26) alkaryl, i.e., the alkyl, alkenyl or alkynyl moiety of the alkaryl group is (C1-C6) and the aryl moiety is (C5-C20). In particularly preferred embodiments the alkaryl group is (C6-C13), i.e., the alkyl, alkenyl or alkynyl moiety of the alkaryl group is (C1-C3) and the aryl moiety is (C5-C10).
xe2x80x9cSubstituted Alkaryl:xe2x80x9d refers to an alkaryl radical wherein one or more hydrogen atoms on the aryl moiety are each independently replaced with another substituent. Typical substituents include, but are not limited to, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(S)NRR, xe2x80x94C(NRR)NR, xe2x80x94NRxe2x80x94C(O)R, xe2x80x94C(NRR)xe2x95x90NOR, xe2x80x94C(O)NROR, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, -halogen and -trihalomethyl, where each R is independently xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroaryl or alk-heteroaryl as defined herein.
xe2x80x9cHeteroaryl:xe2x80x9d refers to an aryl moiety wherein one or more carbon atoms has been replaced with another atom, such as N, P, O, S, As, Ge, Se, Si, Te, etc. Typical heteroaryl groups include, but are not limited to acridarsine, acridine, arsanthridine, arsindole, arsindoline, benzodioxole, benzothiadiazole, carbazole, xcex2-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, isoindole, indolizine, isoarsindole, isoarsinoline, isobenzofuran, isochromane, isochromene, isoindole, isophosphoindole, isophosphinoline, isoquinoline, isothiazole, isoxazole, naphthyridine, perimidine, phenanthridine, phenanthroline, phenazine, phosphoindole, phosphinoline, phthalazine, piazthiole, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, selenophene, tellurophene, thiazopyrrolizine, thiophene and xanthene. In preferred embodiments, the heteroaryl group is a 5-20 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
xe2x80x9cSubstituted Heteroaryl:xe2x80x9d refers to a heteroaryl radical wherein one or more hydrogen atoms are each independently replaced with another substituent. Typical substituents include, but are not limited to, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NRR)xe2x95x90NR, xe2x80x94C(O)NROR, xe2x80x94C(NRR)xe2x95x90NOR, xe2x80x94NRxe2x80x94C(O)R, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, xe2x80x94NRxe2x80x94C(O)xe2x80x94OR, xe2x80x94NRxe2x80x94SO2xe2x80x94R, -tetrazol-5-yl, -halogen and -trihalomethyl where each R is independently xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroaryl and alk-heteroaryl as defined herein.
xe2x80x9cAlk-heteroaryl:xe2x80x9d refers to a straight-chain alkyl, alkenyl or alkynyl group where one of the hydrogen atoms bonded to a terminal carbon atom is replaced with a heteroaryl moiety. In preferred embodiments, the alkheteroaryl group is a 6-26 membered alkheteroaryl, i.e., the alkyl, alkenyl or alkynyl moiety of the alk-heteroaryl is (C1-C6) and the heteroaryl moiety is a 5-20-membered heteroaryl. In particularly preferred embodiments, the alk-heteroaryl is a 6-13 membered alk-heteroaryl, i.e., the alkyl, alkenyl or alkynyl moiety is (C1-C3) and the heteroaryl moiety is a 5-10 membered heteroaryl.
xe2x80x9cSubstituted Alk-heteroaryl:xe2x80x9d refers to an alk-heteroaryl radical wherein one or more hydrogens on the heteroaryl moiety are each independently replaced with another substituent. Typical substituents include, but are not limited to, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(S)NRR, xe2x80x94C(NRR)xe2x95x90NR, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, xe2x80x94NRxe2x80x94C(O)xe2x80x94OR, xe2x80x94NRxe2x80x94SO2xe2x80x94R, -tetrazol-5-yl, -halogen and -trihalomethyl, where each R is independently xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroaryl or alk-heteroaryl as defined herein.
xe2x80x9cElectron-donating functional groupxe2x80x9d An electron-donating functional group is any functional group that produces an inductive field effect by presenting a partial negative charge to the parent group that the functional group is attached to. As used herein, representative electron-donating groups include, but are not limited to, xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, and xe2x80x94NRR, where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl.
xe2x80x9cElectron-withdrawing functional groupxe2x80x9d An electron-withdrawing functional group is any functional group that produces an inductive field effect by presenting a partial positive charge to the parent group that the functional group is attached to. As used herein, representative electron-withdrawing functional groups include, but are not limited to, xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, xe2x80x94SO2NHR, xe2x80x94SO2R, and xe2x80x94S(O)R, where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl.
xe2x80x9cLower Alkylxe2x80x9d defines branched or unbranched organic compounds with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.
xe2x80x9cA lower alkyl groupxe2x80x9d is branched or unbranched and contains 1 to 7 carbon atoms, preferably 1-4 carbon atoms, and represents for example methyl, ethyl, propyl, butyl, isopropyl, isobutyl and the like.
xe2x80x9cCarbocylic arylxe2x80x9d represents monocyclic or bicyclic aryl, for example phenyl or phenyl mono-, di- or tri-substituted by one, two or three radicals selected from lower alkyl, lower alkoxy, hydroxy, halogen, cyano and trifluoromethyl or phenyl disubstituted on adjacent carbon atoms by lower alkylenedioxy, such as methylenedioxy; or 1- or 2-naphthyl. Preferred is phenyl or phenyl monosubstituted by lower alkoxy, halogen or trifluoromethyl.
xe2x80x9cHeterocyclic arylxe2x80x9d represents monocyclic or bicyclic heteroaryl, for example pyridyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrrazolyl, imidazolyl, thienyl, or any said radical substituted by lower alkyl or halogen. Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl, advantageously 2-thienyl. Quinolyl represents preferably 2-, 3- or 4-quinolyl, advantageously 2-quinolyl. Isoquionolyl represents preferably 1-, 3- or 4-isoquinolyl. Benzopyranyl, benzothiopyranyl represents preferably 3-benzopyranyl or 3-benzothiopyranyl, respectively. Thiazolyl represents preferably 2- or 4-thiazolyl, advantageously 4-thiazolyl. Triazolyl is preferably 1-, 2- or 5-(1,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl. Imidazolyl is preferably 4-imidazolyl.
xe2x80x9cBiarylxe2x80x9d is preferably carbocyclic biaryl, e.g. biphenyl, namely 2, 3 or 4-biphenyl, advantageously 4-biphenyl, each optionally substituted by e.g. lower alkyl, lower alkoxy, halogen, trifluoromethyl or cyano.
xe2x80x9cC3-C7-cycloalkylxe2x80x9d represents a saturated cyclic hydrocarbon optionally substituted by lower alkyl which contains 3 to 7 ring carbons and is advantageously cyclopentyl or cyclohexyl optionally substituted by lower alkyl.
xe2x80x9cCarbocyclic aryl-lower alkylxe2x80x9d represents preferably straight chain or branched aryl-C1-C4 alkyl in which carbocyclic aryl has meaning as defined above, e.g. benzyl or phenyl-(ethyl, propyl or butyl), each unsubstituted or substituted on the phenyl ring as defined under carbocyclic aryl above, advantageously optionally substituted benzyl.
xe2x80x9cHeterocyclic aryl-lower alkylxe2x80x9d represents preferably straight chain or branched heterocyclic aryl-C1-C4-alkyl in which heterocyclic aryl has meaning as defined above, e.g. 2-, 3-, or 4-pyridylmethyl or (2-, 3-, or 4-pyridyl)-(ethyl, propyl or butyl); or 2- or 3-thienylmethyl or (2- or 3-thienyl)-(ethyl, propyl or butyl); 2-, 3-, or 4-quinolylmethyl or (2-, 3- or 4-quinolyl)-(ethyl, propyl or butyl); or 2- or 4-thiazolylmethyl or (2- or 4-thiazolyl)-(ethyl, propyl or butyl); and the like.
xe2x80x9cCycloalkyl-lower alkylxe2x80x9d represents preferably (cyclopentyl- or cyclohexyl)-(methyl or ethyl), and the like.
xe2x80x9cBiaryl-lower alkylxe2x80x9d represents preferably 4-biphenylyl-(methyl or ethyl) and the like.
The present invention provides a novel class of organic compounds capable of inhibiting the enzyme C-proteinase, pharmaceutical compositions comprising one or more of such compounds, and methods of using the compounds to inhibit, regulate or modulate collagen formation or maturation as a therapeutic approach towards the treatment or prevention of diseases related to, or associated with, unregulated collagen production or maturation.
In one embodiment, compounds which are capable of inhibiting C-proteinase according to the invention, and which can therefore be used in methods to inhibit, modulate or regulate collagen production or maturation or to treat or prevent diseases related to, or associated with, unregulated collagen production or maturation are generally N-aryl substituted arylsulfonylamino hydroxamic acids having the structural formula (I): 
or pharmaceutically acceptable salts thereof, wherein:
a is an integer from 1 to 4;
b is an integer from 0 to 4;
c is an integer from 0 to 4;
Ar1 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y1, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y2;
Ar2 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y2, 5-20 membered heteroaryl, and 5-20 membered heteroaryl independently substituted with one or more Y2;
each Y1 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group; and
each Y2 is independently selected from the group consisting of a functional group having an acidic hydrogen, a functional group capable of participating in a hydrogen bond, a polar functional group, an electron-withdrawing functional group, an electron-donating functional group, and a lipophilic functional group;
with the provisos that:
(i) when a and b are each one, c is zero and Ar2 is 4xe2x80x2-methoxyphenyl, then Arl is other than phenyl, 4xe2x80x2-flourophenyl, 4xe2x80x2-chlorophenyl, 4xe2x80x2-trifluoromethylphenyl or 4xe2x80x2-methoxyphenyl; (ii) when a and b are each one, c is zero and Ar2 is phenyl, then Ar1 is other than 4xe2x80x2-chlorophenyl;
(iii) when a is two, b and c are each zero and Ar1 is phenyl, then Ar2 is other than 41-chlorophenyl or 4xe2x80x2-bromophenyl; and
(iv) when a and b are each one, c is zero then Ar1 is other than carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, or (N-aryl-lower alkylpiperazino)-lower alkyl,
wherein, in proviso (iv), aryl represents monocyclic or bicyclic aryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclic aryl and heterocyclic aryl represents monocyclic or bicyclic heterocyclic aryl.
Typical electron-donating functional groups that are independently selected for Y1 and Y2 in compounds of formula (I) include, but are not limited to, xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl, and xe2x80x94OCH3.
Functional groups having an acidic hydrogen that are suitable for Y2 in compounds of formula (I) include, but are not limited to, xe2x80x94COOH, xe2x80x94SO3H, xe2x80x94P(O) (OH)2, xe2x80x94C(O)xe2x80x94NHxe2x80x94OH, 
where each R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl, and 6-26 membered alk-heteroaryl as defined herein. Functional groups capable of participating in a hydrogen bond that are suitable for Y2 in compounds of formula (I) include both hydrogen-donating groups and hydrogen accepting groups. Typical hydrogen donating groups independently selected for Y2 include, but are not limited to, xe2x80x94C(NHR)xe2x95x90Nxe2x80x94OH, xe2x80x94NHxe2x80x94C(O)R, xe2x80x94NHxe2x80x94C(O)xe2x80x94NRR, xe2x80x94C(S)NHR, xe2x80x94C(O)NHR, xe2x80x94CO2H, xe2x80x94NH2, xe2x80x94C(NHR)xe2x95x90NR, xe2x80x94NHxe2x80x94C(O)xe2x80x94OR, xe2x80x94NHxe2x80x94SO2xe2x80x94R, xe2x80x94NHxe2x80x94C(S)xe2x80x94NRR where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl, and 6-26 membered alk-heteroaryl as defined herein. Typical hydrogen accepting groups selected for Y2 include, but are not limited to, xe2x80x94CO2R, SO2R, xe2x80x94OR, SR, C(O)xe2x80x94R, xe2x80x94C(O)NRR, xe2x80x94C(S)NRR, xe2x80x94NHxe2x80x94C(O)R, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, xe2x80x94NRxe2x80x94C(S)xe2x80x94NRR, and xe2x80x94S(O)xe2x80x94R where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein. Typical polar functional groups selected for Y2 in compounds of formula (I) include, but are not limited to xe2x80x94Cxe2x89xa1N, xe2x80x94OR, and xe2x80x94SR where R is independently xe2x80x94H, (C1xe2x80x94C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical electron-withdrawing functional groups that are independently selected for Y1 and Y2 in compounds of formula (I) include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, and xe2x80x94SO2NHR; where each R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein. Furthermore, groups such as xe2x80x94SO2R and xe2x80x94S(O)R may be selected for Y2.
Typical lipophilic functional groups that are selected for Y1 and Y2 include, but are not limited to n-butyl, alkoxy such as butoxy, and halogen.
One group of preferred compounds according to structure (I) are those compounds wherein Ar1 is selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more Y1 and Ar2 is selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more Y2. Particularly preferred compounds according this aspect of the invention are those compounds having the structural formula (Ia): 
or pharmaceutically acceptable salts thereof, wherein:
a is an integer from 1 to 4;
b is an integer from 0 to 4;
c is an integer from 0 to 4;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of xe2x80x94H, an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group;
R6, R7, R8, R9 and R10 are each independently selected from the group consisting of xe2x80x94H, a functional group having an acidic hydrogen, a functional group capable of participating in a hydrogen bond (e.g., a hydrogen-donating or a hydrogen-accepting functional group), a polar functional group, an electron-withdrawing functional group, an electron-donating functional group, and a lipophilic functional group;
with the provisos that
(i) when a and b are each one, c is other than zero; and
(ii) when a is two, b and c are each zero and R1, R2, R4, R5, R6, R7, R9 and R10 are each xe2x80x94H, then R8 is other than xe2x80x94F or xe2x80x94Cl.
Electron-donating functional groups useful for substituting the A-phenyl ring of compounds according to structure (Ia) include xe2x80x94R, xe2x80x94Cl, xe2x80x94OR, xe2x80x94SR, and xe2x80x94NRR, where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Functional groups having an acidic hydrogen useful for substituting the B-phenyl ring of compounds according to structure (Ia) include xe2x80x94COOH, xe2x80x94SO3H, xe2x80x94P(O) (OH)2, xe2x80x94C(O)xe2x80x94NHxe2x80x94OH, 
where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C20) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein; and COOH is particularly preferred. Hydrogen-donating/accepting functional groups useful for substituting the B-phenyl ring of compounds according to structure (Ia) include xe2x80x94C(NHR)xe2x95x90Nxe2x80x94OH, xe2x80x94NHxe2x80x94C(O)R, xe2x80x94NHxe2x80x94C(O)xe2x80x94NRR, xe2x80x94C(S)NHR, xe2x80x94C(O)NHR, xe2x80x94CO2H, xe2x80x94NH2, xe2x80x94C(NHR)xe2x95x90NR, xe2x80x94NHxe2x80x94(CO)xe2x80x94OR and xe2x80x94NHxe2x80x94SO2xe2x80x94R, with xe2x80x94NHxe2x80x94C(O)xe2x80x94NRR being particularly preferred. Polar functional groups useful for substituting the B-phenyl ring of compounds according to structure (Ia) include xe2x80x94Cxe2x89xa1N, xe2x80x94OR, and, xe2x80x94SR, with xe2x80x94OR being particularly preferred. Electron-withdrawing functional groups useful for substituting the B-phenyl ring of compounds according to structure (Ia) include xe2x80x94SO2R, xe2x80x94S(O)R, xe2x80x94NO2, and xe2x80x94CF3, with xe2x80x94SO2R being particularly preferred.
One group of preferred compounds according to structure (Ia) are those compounds wherein the A- and/or B-phenyl rings are either unsubstituted or mono-substituted. When mono-substituted, the A-phenyl ring may be substituted at either the ortho, meta or para position; however, para-substitution is preferred. When mono-substituted, the B-phenyl ring may also be substituted at the ortho, meta or para position, with para-substitution being preferred.
Another group of preferred compounds according to structure (Ia) are those compounds wherein the A-phenyl ring is di-substituted (preferably at the meta- and para-positions) and/or the B-phenyl ring is either unsubstituted or mono-substituted (preferably at the para-position).
Another group of preferred compounds according to structure (Ia) are those compounds having the structural formula (Iaxe2x80x2) 
or pharmaceutically acceptable salts thereof, wherein:
a is an integer from 1 to 4;
b is an integer from 0 to 4;
R3, R4 and R5 are each independently selected from the group consisting of xe2x80x94H, an electron-donating functional group, an electron-withdrawing functional group and a lipophilic functional group; and
R6, R7 and R8 are each independently selected from the group consisting of xe2x80x94H, a functional group having an acidic hydrogen, a functional group capable of participating in a hydrogen bond (e.g., a hydrogen-donating or a hydrogen-accepting functional group), a polar functional group, an electron-withdrawing functional group, an electron-donating functional group, and a lipophilic functional group; with the provisos that
(i) when a is 1, b is other than 1; and
(ii) when a is two and b is zero and R3, R4, R5, R6, R7 are each xe2x80x94H, then R8 is other than xe2x80x94F or xe2x80x94Cl.
One group of preferred compounds according to structure (Iaxe2x80x2) are those compounds wherein:
a is an integer from 1 to 3;
b is an integer from 0 to 2;
R3 and R4 are each independently selected from the group consisting of xe2x80x94H, halogen (preferably xe2x80x94F or xe2x80x94Cl), xe2x80x94OR and trihalomethyl (preferably xe2x80x94CF3);
R5 is selected from the group consisting of xe2x80x94H and xe2x80x94OR (preferably xe2x80x94H);
R6 is selected from the group consisting of xe2x80x94H, xe2x80x94C(O)OR, xe2x80x94C(NH2)xe2x95x90NOH and xe2x80x94SO2R;
R7 is selected from the group consisting of xe2x80x94H and xe2x80x94C(NH2)xe2x95x90NOH; and/or
R8 is selected from the group consisting of xe2x80x94H, xe2x80x94OR, xe2x80x94NO2, xe2x80x94C(O)OR, xe2x80x94SO2R and xe2x80x94C(NH2)xe2x95x90NOH; and
each R is independently selected from the group consisting of xe2x80x94H and (C1-C3) alkyl (preferably methyl), (C2-C3) alkenyl and (C1-C3) alkynyl;
with the provisos that
(i) when a is 1, b is other than 1; and
(ii) when a is two and b is zero and R3, R4, R5, R6, R7 are each xe2x80x94H, then Re is other than xe2x80x94F or xe2x80x94Cl.
Particularly preferred compounds according to structure (Iaxe2x80x2) are as follows:
In another preferred embodiment of the compounds of structure (I), Ar1 is (C1-C6) alkoxyphenyl (particularly 4xe2x80x2-(C1-C6) alkoxyphenyl). Particularly preferred compounds according to this aspect of the invention are those compounds having the structural formula (Ib): 
or pharmaceutically acceptable salts thereof, wherein:
a, b, c and Ar2 are as previously defined for structure (I).
One group of preferred compounds according to structure (Ib) are those compounds wherein:
a, b and c are as previously defined for structure (I);
Ar2 is selected from the group consisting of (C5-C10) aryl, (C5-C10) aryl mono-substituted with Y2, 5-10 membered heteroaryl and 5-10 membered heteroaryl mono-substituted with Y2;
each Y2 is independently selected from the group consisting of xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94NO2, xe2x80x94CN, halogen, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, tetrazole, trihalomethyl, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NRR)xe2x95x90NOR, xe2x80x94C(O)NROR and xe2x80x94SO2R; and
each R is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl,
with the provisos that when a and b is 1 then c is other than 0;
Another preferred group of compounds according to structure (Ib) are those compounds wherein:
a, b and c are as previously defined for structure (I);
Ar2 is selected from the group consisting of phenyl, phenyl momo-substituted with Y2, thienyl and thienyl mono-substituted with Y2;
each Y2 is independently selected from the group consisting of xe2x80x94OR, xe2x80x94NRR, xe2x80x94NO2, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, tetrazole, xe2x80x94CN, halogen, thrihalomethyl, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NH2)xe2x95x90NOH, xe2x80x94C(O)NHOR and xe2x80x94SO2R; and
each R is independently selected from the group consisting of (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl.
Particularly preferred compounds according to structure (Ib) are as follows:
In still another preferred embodiment of the compounds of structure (I), Ar2 is mono- or di-substituted phenyl. Particularly preferred compounds according to this aspect of the invention are those compounds having the structural formula (Ic): 
or pharmaceutically acceptable salts thereof, wherein:
Ar1, a, b and c are as previously defined for structure (I);
R11, R12 and R13 are each independently selected from the group consisting of xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94NO2, xe2x80x94CN, halogen, trihalomethyl, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NRR)xe2x95x90NOR, xe2x80x94NRxe2x80x94C(O)R, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, xe2x80x94NRxe2x80x94C(O)xe2x80x94OR, tetrazol-5-yl, xe2x80x94NRxe2x80x94SO2xe2x80x94R, and xe2x80x94SO2R; and
each R is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl.
One preferred embodiment of the compounds of structure (Ic) are those compounds wherein at least two of R11, R12 and R13 are xe2x80x94H:
Another preferred embodiment of the compounds of structure (Ic) are those compounds according to structure (Icxe2x80x2): 
and pharmaceutically acceptable salts thereof, wherein:
a, b, Ar1, R11, R12 and R13 are as previously defined for structure (Ic).
One particularly preferred group of compounds according to structure (Icxe2x80x2) are those compounds wherein:
a, b and c are as previously defined for structure (I);
Ar1 is selected from the group consisting of phenyl, pyridinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, thienyl and the above-described heteroaryl groups which are independently substituted (preferably mono-substituted) with one or more Y1 groups;
R11, R12 and R13 are each independently selected from the group consisting of xe2x80x94H, xe2x80x94OR, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NH2)NOH, xe2x80x94NHxe2x80x94C(O)R, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRR, xe2x80x94NRxe2x80x94C(O)xe2x80x94OR, xe2x80x94NRxe2x80x94SO2xe2x80x94R, tetrazol-5-yl and xe2x80x94SO2R; and
each R is independently selected from the group consisting of hydrogen, (C1-C3) alkyl (preferably methyl), (C2-C3) alkenyl and (C2-C3) alkynyl.
Another particularly preferred group of compounds according to structure (Icxe2x80x2) are as follows:
In another embodiment, the compounds that are capable of inhibiting c-proteinase according to the invention, and which can therefore be used in methods to inhibit, modulate or regulate collagen production or maturation or to treat diseases related to, or associated with, unregulated collagen production or maturation are generally N-aryl substituted arylsulfonylamino hydroxamic acids having the structural formula (II): 
or pharmaceutically acceptable salts thereof, wherein:
d is an integer from 1 to 4;
e is an integer from 0 to 4;
f is an integer from 0 to 4;
Ar3 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y3, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y3;
Ar4 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y4, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y4;
each Y3 is independently selected from the group consisting of xe2x80x94SO2NH2, xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen and trihalomethyl;
each Y4 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, and xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl; and
each Rxe2x80x3 is independently selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, halogen or trihalomethyl groups,
with the provisos that:
(i) when d and e are each one, f is zero and Ar4 is 4xe2x80x2-methoxyphenyl, then Ar3 is other than phenyl, 4xe2x80x2-fluorophenyl, 4xe2x80x2-chlorophenyl, 4xe2x80x2-trifluoromethylphenyl or 4xe2x80x2-methoxyphenyl;
(ii) when d and e are each one, f is zero and Ar4 is phenyl, then Ar3 is other than 4xe2x80x2-chlorophenyl;
(iii) when d is two, d and e are each zero and Ar3 is phenyl, then Ar4 is other than 4xe2x80x2-chlorophenyl or 4xe2x80x2-bromophenyl; and
(iv) when d and e are each one, f is zero then Ar3 is other than carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, or (N-aryl-lower alkylpiperazino)-lower alkyl
wherein, in proviso (iv), aryl represents monocyclic or bicyclic aryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclic aryl and heterocyclic aryl represents monocyclic or bicyclic heterocyclic aryl.
In one group of preferred compounds according to structure (II), Ar3 is thienyl. Particularly preferred compounds according to this aspect of the invention are those compounds having the structural formula (IIa): 
or pharmaceutically acceptable salts thereof, wherein d, e, f and Ar4 are as previously defined for structure (II).
One group of preferred compounds according to structure (IIa) are those compounds wherein:
d, e and f are as previously defined for structure (II);
Ar4 is selected from the group consisting of phenyl, phenyl independently mono- or di-substituted with Y4, 5-10 membered heteroaryl and 5-10 membered heteroaryl independently mono- or di-substituted with Y4;
each Y4 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl; and
each Rxe2x80x3 is independently selected from the group consisting of phenyl and phenyl independently mono- or di-substituted with halogen, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2 or xe2x80x94CN.
Another group of preferred compounds according to structure (IIa) are those compounds wherein d is two, e is two and/or f is zero.
Another group of preferred compounds according to structure (IIa) are those compounds wherein Ar4 is selected from the group consisting of thienyl (preferably thien-2-yl), 2,1,3-benzothiadiazolyl (also known as piazthiolyl) (preferably 2,1,3-benzothiadiazol-5-yl or piathiol-5-yl), imidazolyl (preferably imidazol-4-yl), 1,7-thiazopyrrolizinyl (preferably 1,7-thiazopyrrolizin-5-yl) and the above-described heteroaryl groups which are independently substituted (preferably mono-substituted) with one or more Y4 groups. Particularly preferred compounds according to this aspect of the invention are as follows:
Another group of preferred compounds according to structure (IIa) are those compounds wherein Ar4 is selected from the group consisting of phenyl and phenyl independently mono-, di- or tri-substituted with Y4. One group of preferred compounds according to this aspect of the invention are those compounds having the structural formula (IIaxe2x80x2): 
or pharmaceutically acceptable salts thereof, wherein:
d, e, and f are as previously defined for structure (IIa);
R14, R15 and R16 are each independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, and xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl; and
Rxe2x80x3 is selected from the group consisting of phenyl and phenyl independently mono-, di-substituted or tri-substituted with halogen or xe2x80x94CN, with the proviso that when d and e are each one, f is other than zero.
One group of preferred compounds according to structure (IIaxe2x80x2) are those compounds wherein d is two, e is two and/or f is zero.
Another group of preferred compounds according to structure (IIaxe2x80x2) are those compounds wherein at least two of R14, R15 and R16 are xe2x80x94H.
Still another group of preferred compounds according to structure (IIaxe2x80x2) are as follows:
Another group of preferred compounds according to structure (II) are those compounds wherein Ar3 is thienyl and Ar4 is thienyl or thienyl independently substituted with one or more Y4. Particularly preferred compounds according to this aspect of the invention are compounds having the structural formulae (IIb) and (IIbxe2x80x2): 
or pharmaceutically acceptable salts thereof, wherein:
d, e and f are as previously defined for structure (II);
R17 is selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxc2x0 C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, and xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2;
Rxe2x80x2 is selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl; and
Rxe2x80x3 is (C5-C10) aryl.
One group of preferred compounds according to structures (IIb) and (IIbxe2x80x2) are those compounds wherein d is two, e two and/or f is zero.
Another group of preferred compounds according to structures (IIb) and (IIbxe2x80x2) are as follows:
Another group of preferred compounds according to structure (II) are those compounds wherein Ar3 is benzodioxole. Particularly preferred compounds according to this aspect of the invention are compounds having the structural formula (IIc): 
or pharmaceutically acceptable salts thereof, wherein d, e, f, and Ar4 are as previously defined for structure (II).
One group of preferred compounds according to structure (IIc) are those compounds wherein:
d, e and f are as previously defined for structure (I);
Ar4 is selected from the group consisting of phenyl, phenyl independently mono- or di-substituted with Y4, 5-10 membered heteroaryl and 5-10 membered heteroaryl mono- or di-substituted with Y4; and
Y4 is as previously defined for structure (II).
Another group of preferred compounds according to structure (IIc) are those compounds wherein d is two, e is one and/or f is zero.
Another group of preferred compounds according to structure (IIc) are those compounds wherein Ar4 is selected from the group consisting of thienyl (preferably thien-2-yl), 2,1,3-benzothiadiazolyl (also known as piazthiolyl) (preferably 2,1,3-benzothiadiazol-5-yl or piathiol-5-yl), imidazolyl (preferably imidazol-4-yl), 1,7-thiazopyrrolizinyl (preferably 1,7-thiazopyrrolizin-5-yl) and the above-described heteroaryl groups which are independently mono- or di-substituted (preferably mono-substituted) with one or more Y4 groups. Particularly preferred compounds of structure (IIc) according to this aspect of the invention are as follows:
Another group of preferred compounds according to structure (IIc) are those compounds wherein Ar4 is selected from the group consisting of phenyl and phenyl independently mono-, di- or tri-substituted with Y4. One group of preferred compounds according to this aspect of the invention are those compounds having the structural formula (IIcxe2x80x2): 
or pharmaceutically acceptable salts thereof, wherein:
d, e, f, R14, R15 and R16 are as previously defined for structure (IIaxe2x80x2).
One group of preferred compounds according to structure (IIcxe2x80x2) are those compounds wherein d is two, e is one and/or f is zero.
Another group of preferred compounds according to structure (IIcxe2x80x2) are those compounds wherein at least two of R14, R15 and R14 are xe2x80x94H.
Yet another group of preferred compounds according to structure (IIcxe2x80x2) are as follows:
Still another group of preferred compounds according to structure (II) are those compounds wherein Ar3 is benzodioxole and AR4 is thienyl or thienyl independently substituted with one or more Y4. Particularly preferred compounds according to this aspect of the invention are compounds having the structural formulae (IId) and (IIdxe2x80x2): 
or pharmaceutically acceptable salts thereof, wherein:
d, e, f are as previously defined for structures (IIb) and (IIbxe2x80x2);
each R17 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, and xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl; and
Rxe2x80x3 is selected from the group consisting of phenyl and phenyl independently mono-, di-substituted or tri-substituted with halogen or xe2x80x94CN.
One preferred group of compounds according to structures (IId) and (IIdxe2x80x2) are those compounds where d is two, e is one and/or f is zero.
Another group of preferred compounds according to structures (IId) and (IIdxe2x80x2) are as follows:
In another embodiment, the compounds which are capable of inhibiting C-proteinase according to the invention, and which can therefore be used in methods to inhibit, modulate or regulate collagen production or maturation or to treat diseases related to, or associated with, unregulated collagen production or maturation are generally N-cycloalkyl or N-heterocycloalkyl substituted arylsulfonylamino hydroxamic acids having the structural formula (III): 
or pharmaceutically acceptable salts thereof, wherein:
g is an integer from 1 to 4;
h is an integer from 0 to 4;
i is an integer from 0 to 4;
Z is selected from the group consisting of (C3-C10) cycloalkyl, (C3-C10) cycloalkyl independently substituted with one or more Y5, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkyl independently substituted with one or more Y5;
Ar6 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y6, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y6;
each Y5 is independently selected from the group consisting of a lipophilic functional group, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl;
each Y6 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, and xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2; and
Rxe2x80x2 and Rxe2x80x3 are as previously defined for structure (II),
with the proviso that when g and h are 1, i is 0, and Ar6 is phenyl, then Z is other than C3-C7-cycloalkyl, C3-C7-cycloalkyl-lower alkyl, N-lower alkyl-piperazino-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl.
One group of preferred compounds according to structure (III) are those compounds wherein g is two and/or i is zero.
Another group of preferred compounds according to structure (III) are those compounds wherein:
Z is adamantyl, cyclohexyl, morpholino, tetrahydrofuranyl, piperidyl and piperidyl mono-substituted with Y5;
Ar6 is selected from the group consisting of phenyl and phenyl mono-substituted with Y6; and
Y5 is xe2x80x94(CH2)n-phenyl, where n is an integer from 0 to 3.
Another group of preferred compounds according to structure (III) are those compounds wherein Ar6 is (C1-C6) alkoxyphenyl. Particularly preferred compounds according to this aspect of the invention are those compounds having the structural formula (IIIa): 
or pharmaceutically acceptable salts thereof, wherein:
g, h and Z are as previously defined for structure (III).
Particularly preferred compounds according to structure (IIIa) are as follows:
In another embodiment, the compounds that are capable of inhibiting C-proteinase according to the invention, and which can therefore be used in methods to inhibit, modulate or regulate collagen production or maturation or to treat diseases related to, or associated with, unregulated collagen production or maturation are generally Nxe2x80x2 substituted urea-arylsulfonylamino hydroxamic acids having the structural formula (IV): 
or pharmaceutically acceptable salts thereof, wherein:
j is an integer from 1 to 4;
k is an integer from 0 to 4;
Ar7 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y7, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y7;
R18 and R19 are each independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C10) cycloalkyl, (C5-C20) aryl, (C5-C20) substituted aryl, (C6-C26) alkaryl, (C6-C26) substituted alkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 membered substituted alk-heteroaryl;
each Y7 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
Typical electron-donating functional groups that are independently selected for Y1 in compounds of formula (IV) include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, and xe2x80x94NRR; where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y7 in compounds of formula (IV) include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl or xe2x80x94SO2NHR; where R is xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C20) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y7 include, but are not limited to n-butyl, alkoxy such as butoxy, and bromo.
One group of preferred compounds according to structure (IV) are those compounds wherein Ar7 is (C5-C20) aryl or (C5-C20) aryl independently substituted with one or more Y1 as defined in formula (IV). Particularly preferred compounds according to this aspect of the invention are those compounds having the structural formula (IVa): 
or pharmaceutically acceptable salts thereof, wherein:
j, k, R18 and R19 are as defined in formula (IV);
R20, R21, R22, R23, R24 are independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
Typical electron-donating functional groups that are independently selected for compounds of formula (IVa) include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, and where each R is independently xe2x80x94H, (C2-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y7 in compounds of formula (IV) include, but are not limited to xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl; and xe2x80x94SO2NHR; where R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y7 include, but are not limited to n-butyl, alkoxy such as butoxy, and bromo.
Another group of preferred compounds according to structure (IV) are those compounds wherein Ar7 is phenyl independently substituted with one or more Y7 as defined in formula (IV). Particularly preferred compounds according to this aspect of the invention are those compounds having the structural formula (IVb): 
or pharmaceutically acceptable salts thereof, wherein:
R18 and R19 are as defined in formula (IV);
R50, R51 and R52 are each independently selected from the group consisting of xe2x80x94H, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94NO2, xe2x80x94CN, halogen, trihalomethyl, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NRR)xe2x95x90NOR, xe2x80x94C(O)NROR, xe2x80x94SO2NRR, and xe2x80x94NRSO2R; and
each R is independently selected from the group consisting of (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl. Particularly preferred compounds according to structure (IVb) are as follows:
In another embodiment, the compounds that are capable of inhibiting C-proteinase according to the invention, and which can therefore be used in methods to inhibit, modulate or regulate collagen production or maturation or to treat diseases related to, or associated with, unregulated collagen production or maturation are urea-hydroxamic acids having the structural formula (V): 
or pharmaceutically acceptable salts thereof, wherein:
l is an integer from 1 to 4;
m is an integer from 0 to 4;
Ar8 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y8, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y8;
each R20 is independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C10) cycloalkyl, (C5-C20) aryl, (C5-C20) substituted aryl, (C6-C26) alkaryl, (C6-C26) substituted alkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 membered substituted alk-heteroaryl;
R21 is independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl; and
each Y8 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
Typical electron-donating functional groups that are independently selected for Y7 in compounds of formula (V) include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, and xe2x80x94NRR; where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y7 in compounds of formula (V) include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, xe2x80x94SO2NHR; where R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y7 in compounds of formula (V) include, but are not limited to n-butyl, alkoxy such as butoxy, and bromo.
In another embodiment, the compounds that are capable of inhibiting C-proteinase according to the invention, and which can therefore be used in methods to inhibit, modulate or regulate collagen production or maturation or to treat diseases related to, or associated with, unregulated collagen production or maturation are benzoyl substituted hydroxamic acids having the structural formula (VI): 
or pharmaceutically acceptable salts thereof, wherein:
n is an integer from 1 to 4;
o is an integer from 0 to 4;
Ar9 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y9, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y9; and
each R25, R26, R27, R28, R29 and Y9 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
Typical electron-donating functional groups that are independently selected for Y9 in compounds of formula (VI) include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, and xe2x80x94NRR, where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y9 in compounds of formula (VI) include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, and xe2x80x94SO2NHR, where R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y9 include, but are not limited to n-butyl, alkoxy such as butoxy, and bromo.
Another group of preferred compounds according to structure (VI) are those compounds wherein Ar9 is phenyl independently substituted with one or more Y8 as defined in formula (VI). Particularly preferred compounds according to this aspect of the invention are those compounds having the structural formula (VIa): 
or pharmaceutically acceptable salts thereof, wherein:
R25, R26, R27, R28, R29 are as defined in formula (VI);
R30, R31 and R32 are each independently selected from the group consisting of xe2x80x94H, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94NO2, xe2x80x94CN, halogen, trihalomethyl, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NRR)xe2x95x90NOR, xe2x80x94C(O)NROR, xe2x80x94SO2NRR, and xe2x80x94NRSO2R; and
each R is independently selected from the group consisting of (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl. A particularly preferred compound according to structure (VIa) is FG 2032: 
In a final embodiment, the compounds that are capable of inhibiting C-proteinase according to the invention, and which can therefore be used in methods to inhibit, modulate or regulate collagen production or maturation or to treat diseases related to, or associated with, unregulated collagen production or maturation are benzylsulfonyl substituted hydroxamic acids having the structural formula (VII): 
or pharmaceutically acceptable salts thereof, wherein:
p is an integer from 1 to 4;
q is an integer from 0 to 4;
Ar10 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y10, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y10; and
each R33, R34, R35, R36, R37 and Y10 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
Typical electron-donating functional groups that are independently selected for Y10 in compounds of formula (VII) include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, and where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y10 in compounds of formula (VII) include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, and xe2x80x94SO2NHR; where R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y10 include, but are not limited to n-butyl, alkoxy such as butoxy, and bromo. A group of preferred compounds according to structure (VII) are those compounds wherein Ar10 is phenyl independently substituted with one or more Y10 as defined in formula (VII). Particularly preferred compounds according to this aspect of the invention are those compounds having the structural formula (VIIa): 
or pharmaceutically acceptable salts thereof, wherein:
R33, R34, R35, R36, R37 are as defined in formula (VII);
R38, R39 and R40 are independently selected from the group consisting of xe2x80x94H, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, xe2x80x94NO2, xe2x80x94CN, halogen, trihalomethyl, xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94C(O)NRR, xe2x80x94C(NRR)xe2x95x90NOR, xe2x80x94C(O)NROR, xe2x80x94SO2NRR, and xe2x80x94NRSO2R; and
each R is independently selected from the group consisting of (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl. Particularly preferred compounds according to structure (VIIa) is FG 2033: 
The chemical structural formulae referred to herein may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or stereo isomerism. As the formulae drawings within this specification can only represent one of the possible tautomeric, conformational isomeric, geometric isomeric or stereo isomeric forms, it should be understood that the invention encompasses any tautomeric, conformational isomeric, geometric isomeric or stereo isomeric forms which exhibit biological or pharmacological activity as defined herein.
The compounds of the invention may be in the form of free acids, free bases or pharmaceutically effective acid addition or base addition salts. Such acid addition salts can be readily prepared by treating a compound with a pharmaceutically acceptable acid. Pharmaceutically acceptable acids include, by way of example and not limitation, inorganic acids such as hydrohalic acids (hydrochloric, hydrobromic, etc.), sulfuric acid, nitric acid, phosphoric acid, etc.; and organic acids such as acetic acid, propanoic acid, 2-hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propandioic acid, butandioic acid, etc. Conversely, the acid addition salt can be converted into the free base form by treatment with alkali. Appropriate base addition salts can be readily prepared by treating a compound with a pharmaceutically acceptable base.
In addition to the above compounds and their pharmaceutically acceptable salts, the invention is further directed, where applicable, to solvated as well as unsolvated forms of the compounds (e.g. hydrated forms) exhibiting biological or pharmacological activity as defined herein.
The compounds of the invention may be prepared by any process known to be applicable to the preparation of chemical compounds. Suitable processes are well-known in the art. See e.g., Tamura et al., 1998, J. Med. Chem. 41:640-649; MacPherson et al., 1997, J. Med. Chem. 40:2525-2532; and WO96/27583. Preferred processes are illustrated by the representative examples. Necessary starting materials may be obtained commercially or by standard procedures of organic chemistry.
By way of example, the compounds of the invention can be conveniently prepared by schemes (I) thru (XV) below: 
In Scheme (I),
b is an integer from 0 to 4;
c is an integer from 0 to 4;
Ar1 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y1, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y1;
Ar2 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y2, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y2;
each Y1 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group;
each Y2 is independently selected from the group consisting of a functional group having an acidic hydrogen, a functional group capable of participating in a hydrogen bond, a polar functional group, an electron-withdrawing functional group, an electron-donating functional group, and a lipophilic functional group; and
R is methyl or ethyl.
According to Scheme (I), methyl acrylate or ethyl acrylate 1 is added to a solution of a primary amine 2 in ethanol. The mixture is heated to reflux (ca. 90xc2x0 C.) for 20 h and then concentrated. The residue 3 is dissolved in methylene chloride (2.8 mL/mmol), followed by the addition of sulfonyl chloride 4 (1 eq.) and Amberlyst (A-21) weakly basic ion exchange resin (0.8 g/mmol). The mixture is vortexed overnight at room temperature (ca. 18 h), monitored by TLC by observing the disappearance of sulfonyl chloride. The reaction mixture is filtered and concentrated to yield residue 5. To 5 is added 2 equivalents of freshly prepared neutralized NH2OH (1 M in methanol). The mixture is vortexed overnight (monitored by TLC), concentrated, followed by work up procedure and/or chromatographic purification to afford 6. Two work up procedures are set up depending upon the feature of the product.
Hydrophobic compounds 6 are treated with 1 N HCl solution and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is then triturated with ether to remove undesired products which are discarded. The solid is collected and dried in vacco.
Hydrophilic compounds 6 are triturated with ethyl acetate twice. Ethyl acetate is decanted and discarded. The residue is treated with water, neutralized by 1 N HCl solution to pH=7-8, and extracted with 10/1 ethyl acetate/methanol. The combined organic layers is washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is triturated in ether, which is discarded, and dried in vacco to furnish the product as a white solid.
In the case that a solid product formed during the work up process, the solid is collected, washed with ethyl acetate and dried in vacco. In the case that TLC indicates low purity of the desired product, purification is conducted using silica gel chromatography and/or recrystallization. 
In Scheme (II),
e is an integer from 0 to 4;
f is an integer from 0 to 4;
Ar3 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y3, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y3;
Ar4 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y4, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y4;
each Y3 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen and trihalomethyl;
each Y4 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl;
each Rxe2x80x3 is independently selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, halogen or trihalomethyl groups; and
R is methyl or ethyl.
According to Scheme (II), methyl acrylate or ethyl acrylate 7 is added to a solution of a primary amine 8 in ethanol. The mixture is heated to reflux (ca. 90xc2x0 C.) for 20 h and then concentrated. The residue 9 is dissolved in methylene chloride (2.8 mL/mmol), followed by the addition of sulfonyl chloride 10 (1 eq.) and Amberlyst (A-21) weakly basic ion exchange resin (0.8 g/mmol). The mixture is vortexed overnight at room temperature (ca. 18 h), monitored by TLC by observing the disappearance of sulfonyl chloride. The reaction mixture is filtered and concentrated to yield residue 11. To 11 is added 2 equivalents of freshly prepared neutralized NH2OH (1 M in methanol). The mixture is vortexed overnight (monitored by TLC), concentrated, followed by a work up procedure and/or chromatographic purification to afford 12. The work up procedure used depended upon the hydrophobicity of the product:
Hydrophobic compounds 12 are treated with 1 N HCl solution and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is then triturated with ether to remove undesired products which are discarded. The solid is collected and dried in vacco.
Hydrophilic compounds 12 are triturated with ethyl acetate twice. Ethyl acetate is decanted and discarded. The residue is treated with water, neutralized by 1 N HCl solution to pH=7-8, and extracted with 10/1 ethyl acetate/methanol. The combined organic layers is washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is triturated in ether, which is discarded, and dried in vacco to furnish the product as a white solid.
In the case that solid product formed during work up process, the solid is collected, washed with ethyl acetate and dried in vacco. In the case that TLC indicates low purity of the desired product, purification is conducted using silica gel chromatography and/or recrystallization. 
In Scheme (III)
h is an integer from 0 to 4;
i is an integer from 0 to 4;
Z is selected from the group consisting of (C3-C10) cycloalkyl, (C3-C10) cycloalkyl independently substituted with one or more Y5, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkyl independently substituted with one or more Y5;
Ar6 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y6, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y6;
each Y5 is independently selected from the group consisting of a lipophilic functional group, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl;
each Y6 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2;
xe2x80x94Rxe2x80x2 and Rxe2x80x3 are as previously defined for Scheme (II); and R is methyl or ethyl.
According to Scheme (III), methyl acrylate or ethyl acrylate 13 is added to a solution of a primary amine 14 in ethanol. The mixture is heated to reflux (ca. 90xc2x0 C.) for 20 h and then concentrated. The residue 15 is dissolved in methylene chloride (2.8 mL/mmol), followed by the addition of sulfonyl chloride 16 (1 eq.) and Amberlyst (A-21) weakly basic ion exchange resin (0.8 g/mmol). The mixture is vortexed overnight at room temperature (ca. 18 h), monitored by TLC by observing the disappearance of sulfonyl chloride. The reaction mixture is filtered and concentrated to yield residue 17. To 17 is added 2 equivalents of freshly prepared neutralized NH2OH (1 M in methanol). The mixture is vortexed overnight (monitored by TLC), concentrated, followed by work up procedure and/or chromatographic purification to afford 18. The work up procedure used depended upon the hydrophobicity of the product:
Hydrophobic compounds 18 are treated with 1 N HCl solution and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is then triturated with ether to remove undesired products which are discarded. The solid is collected and dried in vacco.
Hydrophilic compounds 18 are triturated with ethyl acetate twice. Ethyl acetate is decanted and discarded. The residue is treated with water, neutralized by 1 N HCl solution to pH=7-8, and extracted with 10/1 ethyl acetate/methanol. The combined organic layers is washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is triturated in ether, which is discarded, and dried in vacco to furnish the product as a white solid.
In the case that solid product formed during work up process, the solid is collected, washed with ethyl acetate and dried in vacco. In the case that TLC indicates low purity of the desired product, purification is conducted using silica gel chromatography and/or recrystallization. 
In Scheme (IV),
a is an integer from 1 to 4;
b is an integer from 0 to 4;
c is an integer from 0 to 4;
Ar1 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y1, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y1;
Ar2 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y2, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y2;
each Y1 is independently selected from the group consisting of an electron-donating functional group, an electron-accepting functional group, and a lipophilic functional group;
each Y2 is independently selected from the group consisting of a functional group having an acidic hydrogen, a functional group capable of participating in a hydrogen bond, a polar functional group, an electron-withdrawing functional group, an electron-donating functional group, and a lipophilic functional group;
R is methyl or ethyl; and
X is chloro or bromo.
According to Scheme (IV), a primary amine 19 is dissolved in methylene chloride, followed by the addition of sulfonyl chloride 20 and Amberlyst weakly basic ion exchange resin to yield compound 21. Compound 21 is dissolved in dry DMF and stirred under argon. To this mixture is added sodium hydride 60% suspended in mineral oil and the resulting mixture stirred. To this mixture is added compound 22 to yield compound 23 after silica gel chromatography. To compound 23 is added freshly prepared NH2OH (1 M in methanol). The mixture is stirred to afford compound 24. Depending on the chemical properties of compound 24, it is worked up as follows.
Hydrophobic compounds 24 are treated with a HCl solution and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is then triturated with ether to remove undesired products which are discarded. The solid is collected and dried in vacco.
Hydrophilic compounds 24 are triturated with ethyl acetate twice. Ethyl acetate is decanted and discarded. The residue is treated with water, neutralized by 1 N HCl solution to pH=7-8, and extracted with 10/1 ethyl acetate/methanol. The combined organic layers is washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is triturated in ether, which is discarded, and dried in vacco to furnish the product as a white solid. 
In Scheme (V),
d is an integer from 1 to 4;
e is an integer from 0 to 4;
f is an integer from 0 to 4;
Ar3 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y3, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y3;
Ar4 is selected from the group consisting of (C1-C20) aryl, (C5-C20) aryl independently substituted with one or more Y4, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y4;
each Y3 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen and trihalomethyl;
each Y4 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl;
each Rxe2x80x3 is independently selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, halogen or trihalomethyl groups;
R is methyl or ethyl; and
X is chloro or bromo.
According to Scheme (V), a primary amine 25 is dissolved in methylene chloride, followed by the addition of sulfonyl chloride 26 and Amberlyst weakly basic ion exchange resin to yield compound 27. Compound 27 is dissolved in dry DMF and stirred under argon. To this mixture is added sodium hydride 60% suspended in mineral oil and the resulting mixture stirred. To this mixture is added compound 28 to yield compound 29 after silica gel chromatography. To compound 29 is added freshly prepared NH2OH (1 M in methanol). The mixture is stirred to afford compound 30. Depending on the chemical properties of compound 30, it is worked up as follows:
Hydrophobic compounds 30 are treated with a HCl solution and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is then triturated with ether to remove undesired products which are discarded. The solid is collected and dried in vacco.
Hydrophilic compounds 30 are triturated with ethyl acetate twice. Ethyl acetate is decanted and discarded. The residue is treated with water, neutralized by 1 N HCl solution to pH=7-8, and extracted with 10/1 ethyl acetate/methanol. The combined organic layers is washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is triturated in ether, which is discarded, and dried in vacco to furnish the product as a white solid. 
In Scheme (VI),
g is an integer from 1 to 4;
h is an integer from 0 to 4;
i is an integer from 0 to 4;
Z is selected from the group consisting of (C3-C10) cycloalkyl, (C3-C10) cycloalkyl independently substituted with one or more Y5, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkyl independently substituted with one or more Y5;
Ar6 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y6, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y6;
each Y5 is independently selected from the group consisting of a lipophilic functional group, (C5-C20) aryl, C5-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl;
each Y6 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl;
each Rxe2x80x3 is independently selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, halogen or trihalomethyl groups;
R is methyl or ethyl; and
X is chloro or bromo.
According to Scheme (VI), a primary amine 31 is dissolved in methylene chloride, followed by the addition of sulfonyl chloride 32 and Amberlyst weakly basic ion exchange resin to yield compound 33. Compound 33 is dissolved in dry DMF and stirred under argon. To this mixture is added sodium hydride 60% suspended in mineral oil and the resulting mixture stirred. To this mixture is added compound 34 to yield compound 35 after silica gel chromatography. To compound 35 is added freshly prepared NH2OH (1 M in methanol). The mixture is stirred to afford compound 36. Depending on the chemical properties of compound 36, it is worked up as follows.
Hydrophobic compounds 36 are treated with a HCl solution and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is then triturated with ether to remove undesired products which are discarded. The solid is collected and dried in vacco.
Hydrophilic compounds 36 are triturated with ethyl acetate twice. Ethyl acetate is decanted and discarded. The residue is treated with water, neutralized by 1 N HCl solution to pH 7-8, and extracted with 10/1 ethyl acetate/methanol. The combined organic layers is washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is triturated in ether, which is discarded, and dried in vacco to furnish the product as a white solid. 
In Scheme (VII),
a is an integer from 1 to 2;
b is an integer from 0 to 4;
c is an integer from 0 to 4;
Ar1 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y1, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y1;
Ar2 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y2, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y2;
each Y1 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group;
each Y2 is independently selected from the group consisting of a functional group having an acidic hydrogen, a functional group capable of participating in a hydrogen bond, a polar functional group, an electron-withdrawing functional group, an electron-donating functional group, and a lipophilic functional group; and
R is methyl or ethyl.
According to Scheme (VII), to a solution of compound 37 in anhydrous methylene chloride at room temperature is added triethyl amine and compound 38. After the mixture is stirred, sodium triacetoxyborohydride is added and the reaction mixture is stirred for additional period of time to yield compound 39. To compound 39 is added compound 40 and triethyl amine. The resulting mixture is stirred and then quenched with citric acid yielding compound 41. To compound 41 in methanol is added freshly prepared NH2OH solution. The mixture is stirred and concentrated to yield compound 42. 
In Scheme (VIII),
d is an integer from 1 to 4;
e is an integer from 0 to 4;
f is an integer from 0 to 4;
Ar3 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y3, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y3;
Ar4 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y4, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y4;
each Y3 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen and trihalomethyl;
each Y4 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, xe2x80x94NRxe2x80x2 xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl;
each Rxe2x80x3 is independently selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, halogen or trihalomethyl groups; and
R is methyl or ethyl.
According to Scheme (VIII), to a solution of compound 43 in anhydrous methylene chloride at room temperature is added triethyl amine and compound 44. After the mixture is stirred, sodium triacetoxyborohydride is added and the reaction mixture is stirred for additional period of time to yield compound 45. To compound 45 is added compound 46 and triethyl amine. The resulting mixture is stirred and then quenched with citric acid yielding compound 47. To compound 47 in methanol is added freshly prepared NH2OH solution. The mixture is stirred and concentrated to yield compound 48. 
In scheme (IX),
g is an integer from 1 to 4;
h is an integer from 0 to 4;
i is an integer from 0 to 4;
Z is selected from the group consisting of (C3-C10) cycloalkyl, (C3-C10) cycloalkyl independently substituted with one or more Y5, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkyl independently substituted with one or more Y5;
Ar6 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y6, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y6;
each Y5 is independently selected from the group consisting of a lipophilic functional group, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl;
each Y6 is independently selected from the group consisting of xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94ORxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94SRxe2x80x3, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, -halogen, -trihalomethyl, trihalomethoxy, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x2, xe2x80x94C(O)NRxe2x80x2ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NORxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94SO2Rxe2x80x3, xe2x80x94NRxe2x80x2xe2x80x94SO2xe2x80x94Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x2, tetrazol-5-yl, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94C(NRxe2x80x2Rxe2x80x2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x2, xe2x80x94S(O)xe2x80x94Rxe2x80x3, and xe2x80x94NRxe2x80x2xe2x80x94C(S)xe2x80x94NRxe2x80x2Rxe2x80x2;
each Rxe2x80x2 is independently selected from the group consisting of xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl;
each Rxe2x80x3 is independently selected from the group consisting of (C5-C20) aryl and (C5-C20) aryl independently substituted with one or more xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x2, xe2x80x94NO2, xe2x80x94CN, halogen or trihalomethyl groups; and
R is methyl or ethyl.
According to scheme (IX), to a solution of compound 49 in anhydrous methylene chloride at room temperature is added triethyl amine and compound 50. After the mixture is stirred, sodium triacetoxyborohydride is added and the reaction mixture is stirred for additional period of time to yield compound 51. To compound 51 is added compound 52 and triethyl amine. The resulting mixture is stirred and then quenched with citric acid yielding compound 53. To compound 53 in methanol is added freshly prepared NH2OH solution. The mixture is stirred and concentrated to yield compound 54. 
In Scheme (X),
k is an integer from 0 to 4;
Ar7 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y7, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y7 
R18 and R19 are independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C10) cycloalkyl, (C5-C20) aryl, (C5-C20) substituted aryl, (C1-C26) alkaryl, (C6-C26) substituted alkaryl, 6-20 membered heteroaryl, 5-20 membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 membered substituted alk-heteroaryl; and
each Y7 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group.
Typical electron-donating functional groups that are independently selected for Y7 in compounds of formula (IV) include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, and where each R is independently xe2x80x94H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y7 in compounds of formula (IV) include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, xe2x80x94SO2NHR; where R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y7 include, but are not limited to n-butyl, alkoxy such as butoxy, and bromo; and
R is methyl or ethyl.
According to Scheme (X), methyl acrylate or ethyl acrylate 55 is added to a solution of a primary amine 56 in ethanol. The mixture is heated to reflux (ca. 90xc2x0 C.) for 20 h and then concentrated. The residue 57 is dissolved in methylene chloride, followed by the addition of 4-(3-substituted-ureido)benzenesulfonyl chloride 58 (1 eq.) and Amberlyst (A-21) weakly basic ion exchange resin (0.8 g/mmol). The mixture is vortexed overnight at room temperature (ca. 18 h), monitored by TLC by observing the disappearance of sulfonyl chloride. The reaction mixture is filtered and concentrated to yield residue 59. To 59 is added 2 equivalents of freshly prepared neutralized NH2OH (1 M in methanol). The mixture is vortexed overnight (monitored by TLC), concentrated, followed by work up procedure and/or chromatographic purification to afford 60. Two work up procedures are set up depending upon the feature of the product.
Hydrophobic compounds 60 are treated with 1 N HCl solution and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is then triturated with ether to remove undesired products which are discarded. The solid is collected and dried in vacco.
Hydrophilic compounds 60 are triturated with ethyl acetate twice. Ethyl acetate is decanted and discarded. The residue is treated with water, neutralized by 1 N HCl solution to pH=7-8, and extracted with 10/1 ethyl acetate/methanol. The combined organic layers is washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is triturated in ether, which is discarded, and dried in vacco to furnish the product as a white solid.
In the case that solid product formed during work up process, the solid is collected, washed with ethyl acetate and dried in vacco. In the case that TLC indicates low purity of the desired product, purification is conducted using silica gel chromatography and/or recrystallization.
Compound 58 is prepared by the following method: To a solution of primary or secondary amine 61 (0.5 mmol) in THF (1 mL) at 0xc2x0 C. was added 4-(chlorosulfonyl)phenyl isocyanate 62 (0.5 mmol). After stirring at 0xc2x0 C. for 2 h, the mixture was concentrated to afford 4-(3-substituted-ureido)benzenesulfonyl chloride 58. 
In Scheme (XI),
j is an integer from 1 to 4;
k is an integer from 0 to 4;
Ar7 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y7, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y7;
R18 and R19 are independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C5-C20) alkynyl, (C3-C10) cycloalkyl, (C5-C20) aryl, (C5-C20) substituted aryl, (C6-C26) alkaryl, (C6-C26) substituted alkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl, 6-26 membered alk-heteroaryl; and 6-26 membered substituted alk-heteroaryl;
each Y7 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group; and
R is methyl or ethyl.
Typical electron-donating functional groups that are independently selected for Y7 in compounds of formula (IV) include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, and xe2x80x94NRR; where each R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y7 in compounds of formula (IV) include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, and xe2x80x94SO2NHR; where R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y7 include, but are not limited to n-butyl, alkoxy such as butoxy, and bromo.
According to Scheme (XI), to a solution of compound 63 in anhydrous methylene chloride at room temperature is added triethyl amine and compound 64. After the mixture is stirred, sodium triacetoxyborohydride is added and the reaction mixture is stirred for additional period of time to yield compound 65. To compound 65 is added compound 66 and triethyl amine. The resulting mixture is stirred and then quenched with citric acid yielding compound 67. To compound 67 in methanol is added freshly prepared NH2OH solution. The mixture is stirred and concentrated to yield compound 68.
Compound 66 is prepared by the following method. To a solution of primary or secondary amine 69 (0.5 mmol) in THF (1 mL) at 0xc2x0 C. was added 4-(chlorosulfonyl)phenyl isocyanate 70 (0.5 mmol). After stirring at 0xc2x0 C. for 2 h, the mixture was concentrated to afford 4-(3-substituted-ureido)benzenesulfonyl chloride 66. 
In Scheme (XII),
j is an integer from 1 to 4;
k is an integer from 0 to 4;
Ar7 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y7, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y7;
R18 and R19 are independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C10) cycloalkyl, (C5-C20) aryl, (C5-C20) substituted aryl, (C6-C26) alkaryl; (C6-C26) substituted alkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 membered substituted alk-heteroaryl;
each Y7 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group;
R is methyl or ethyl; and
X is chloro or bromo.
Typical electron-donating functional groups that are independently selected for Y7 in compounds of formula (XII) include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, and xe2x80x94NRR; where each R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y7 in compounds of formula (XII) include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, and xe2x80x94SO2NR; where R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y7 include, but are not limited to n-butyl, alkoxy such as butoxy, and bromo.
According to Scheme (XII), a primary amine 71 is dissolved in methylene chloride, followed by the addition of benzylsulfonyl chloride 72 and Amberlyst weakly basic ion exchange resin to yield compound 73. Compound 73 is dissolved in dry DMF and stirred under argon. To this mixture is added sodium hydride 60% suspended in mineral oil and the resulting mixture stirred. To this mixture is added compound 74 to yield compound 75 after silica gel chromatography. To compound 75 is added freshly prepared NH2OH (1 M in methanol). The mixture is stirred to afford compound 76. Depending on the chemical properties of compound 76, it is worked up as follows:
Hydrophobic compounds 76 are treated with a HCl solution and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is then triturated with ether to remove undesired products which are discarded. The solid is collected and dried in vacco.
Hydrophilic compounds 76 are triturated with ethyl acetate twice. Ethyl acetate is decanted and discarded. The residue is treated with water, neutralized by 1 N HCl solution to pH=7-8, and extracted with 10/1 ethyl acetate/methanol. The combined organic layers is washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is triturated in ether, which is discarded, and dried in vacco to furnish the product as a white solid.
Preparation of (compound 72) 4-(3-Substituted-ureido)-benzenesulfonyl Chloride: To a solution of primary or secondary amine 77 (0.5 mmol) in THF (1 mL) at 0xc2x0 C. is added 4-(chlorosulfonyl)phenyl isocyanate 78 (0.5 mmol). After stirring at 0xc2x0 C. for 2 h, the mixture was concentrated to afford 4-(3-substituted-ureido)benzenesulfonyl chloride 72. 
In Scheme (XIII),
n is an integer from 1 to 4;
o is an integer from 0 to 4;
Ar9 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y9, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y9;
each R25, R26, R27, R28, R29 and Y9 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group; and
X is chloro or bromo.
Typical electron-donating functional groups that are independently selected for Y9 include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, and xe2x80x94NRR; where each R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y9 include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, and xe2x80x94SO2NHR; where R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y9 include, but are not limited to n-butyl, alkoxy such as butoxy, and halogen.
According to scheme (XIII), to a solution of 79 in 5:1 methanol/ethyl acetate (4.2 mL/mmol) is added by portion palladium (10%) in charcoal solid (10% w/w), followed by ammonium formate (4 eq.). The resulting mixture is refluxed for 6 hours and filtered through a pad of celite. Filtrate is concentrated and partitioned between ethyl acetate and water. Organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated to give 80. To a solution of 80 in acetonitrile (7.8 mL/mmol) is added the corresponding electrophile (1.1 eq.) substituted benzoyl halide 81 followed by triethyl amine (2 eq.). The mixture is stirred at room temperature for 5 hours and then partitioned between methylene chloride and 0.1 N hydrochloric acid aqueous solution. The acid layer is extracted with methylene chloride. Combined organic layers are washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is then treated with 10 equivalents of freshly prepared neutralized NH2OH (1 M in methanol). The mixture is stirred at room temperature for 5 hours and concentrated to yield residue 82. Residue 82 is partitioned between 10:1 ethyl acetate/methanol and 1 N hydrochloric acid aqueous solution. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the corresponding hydroxamic acid 83. 
In Scheme (XIV),
p is an integer from 1 to 4;
q is an integer from 0 to 4;
Ar10 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y8, 5-20 membered heteroaryl and 5-20 membered heteroaryl independently substituted with one or more Y10;
each R33, R34, R35, R36, R37 and Y10 is independently selected from the group consisting of an electron-donating functional group, an electron-withdrawing functional group, and a lipophilic functional group; and
X is chloro or bromo.
Typical electron-donating functional groups that are independently selected for Y10 include, but are not limited to xe2x80x94Cl, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, and xe2x80x94NRR, where each R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. Particularly preferred electron-donating groups are xe2x80x94Cl and xe2x80x94OCH3.
Typical electron-withdrawing functional groups that are independently selected for Y10 include, but are not limited to xe2x80x94F, xe2x80x94NO, xe2x80x94NO2, xe2x80x94CN, -trihalomethyl, and xe2x80x94SO2NHR; where R is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl as defined herein.
Typical lipophilic functional groups that are selected for Y10 include, but are not limited to n-butyl, alkoxy such as butoxy, and bromo.
According to scheme (XIV), to a solution of 84 in 5:1 methanol/ethyl acetate (4.2 mL/mmol) is added by portion palladium (10%) in charcoal solid (10% w/w), followed by ammonium formate (4 eq.). The resulting mixture is refluxed for 6 hours and filtered through a pad of celite. Filtrate is concentrated and partitioned between ethyl acetate and water. Organic layer is then washed with brine, dried over sodium sulfate, filtered and concentrated to give 85. To a solution of 85 in acetonitrile (7.8 mL/mmol) is added the corresponding electrophile (1.1 eq.) substituted benzenesulfonyl halide 86 followed by triethyl amine (2 eq.). The mixture is stirred at room temperature for 5 hours and then partitioned between methylene chloride and 0.1 N hydrochloric acid aqueous solution. The acid layer is extracted with methylene chloride. Combined organic layers are washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield 87. Residue 87 is then treated with 10 equivalents of freshly prepared neutralized NH2OH (1 M in methanol). The mixture is stirred at room temperature for 5 hours and concentrated to yield residue 88. Residue 88 is partitioned between 10:1 ethyl acetate/methanol and 1 N hydrochloric acid aqueous solution. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and concentrated to give isolated hydroxamic acid 88. 
In Scheme (XV),
l is an integer from 1 to 4;
m is an integer from 0 to 4;
Ar8 is selected from the group consisting of (C5-C20) aryl, (C5-C20) aryl independently substituted with one or more Y8, 5-20 membered heteroaryl, and 5-20 membered heteroaryl independently substituted with one or more Y8;
R20 is independently selected from the group consisting of H, (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl; and
R21 is selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C10) cycloalkyl, (C5-C20) aryl, (C5-C20) substituted aryl, (C6-C26) alkaryl, (C6-C26) substituted alkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 membered substituted alk-heteroaryl.
According to Scheme (XV) to a solution of 89 in 5:1 methanol/ethyl acetate (4.2 mL/mmol) is added by portion palladium (10%) in charcoal solid (10% w/w), followed by ammonium formate (4 eq.). The resulting mixture is refluxed for 6 hours and filtered through a pad of celite. Filtrate is concentrated and partitioned between ethyl acetate and water. Organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated to give 90. To a solution of 90 is added aldehyde 91 followed by triethyl amine to yield compound 92. To compound 92 is added compound 93 to yield compound 94. Compound 94 is treated with 10 equivalents of freshly prepared NH2OH (1 M in methanol). The mixture is stirred at room temperature for 5 hours and concentrated to yield residue 95.
An individual compound""s relevant activity and potency as an inhibitor of C-proteinase, to regulate or modulate collagen production or maturation and/or to treat disorders associated with unregulated collagen production may be determined using available techniques.
Typically, active compounds of the invention will inhibit 50% of the activity of C-proteinase at concentrations in the range of 100 micromolar (xcexcM) or less (i.e., those compounds exhibiting an IC50 of 100 xcexcM or less) using standard biochemical assays (Dickson, 1953, Biochem. J. 55:170-171; Knight et al., 1992, FEBS 296:263-266). Those of skill in the art will appreciate that compounds exhibiting lower inhibitory concentrations (IC50s) are generally preferred for pharmacological applications; thus, preferably active compounds will exhibit IC50s that are less than 10 xcexcM, more preferably less than 1 xcexcM, even more preferably less than 100 nanomolar (nM) and even more preferably less than about 10 nM or 1 nM. However, as compounds which exhibit IC50s in the millimolar (mM) range can provide consequential pharmacological benefits, compounds which exhibit IC50s as high as 1 mM to 10 mM are considered to possess biological or pharmacological activity.
Alternatively, an in vitro procollagen assay may be used to determine the level of activity and effect of different compounds of the present invention on C-proteinase activity. In the procollagen assay, about 125 ug radiolabeled (14C) procollagen is added to 10 units/mL of chicken C-proteinase in a solution of 0.1 M Tris-HCl, 0.1 M NaCl, 0.02% Brij-35, and 5 mM CaCl2 in a total volume of 10 xcexcl. The reaction is allowed to proceed for 15 minutes at 35xc2x0 C. and is stopped with one-half volume of 3xc3x97 stop/loading buffer (30 mM EDTA, 30% glycerol, 6% SDS, 0.006% Bromophenol-blue). Subsequently, the samples are heated to 100xc2x0 C. for 4 minutes, and resolved by SDS-PAGE (Novex) using 6% polyacryleamide gels. The protein bands are detected by autoradiography. The amount of enzyme activity is based on the disappearance of the band corresponding to uncleaved procollagen. The IC50 of inhibitors can be determined by plotting the % activity versus inhibitor concentration and estimating the inhibitor concentration which results in 50% activity.
Disorders associated with unregulated collagen production or maturation can be treated with the compounds and compositions of the present invention. While not intending to be bound by any particular theory, it is believed that when administered to an animal subject, including a human, the compounds of the invention inhibit C-proteinase in vivo, thereby effectively modulating, regulating or inhibiting collagen production or maturation. As a consequence, the compounds are able to treat or prevent disorders associated with unregulated collagen production or maturation.
Collagen-related disorders which can be treated or prevented according to the invention include pathological fibrosis or scarring, such as endocardial sclerosis, idiopathic interstitial fibrosis, interstitial pulmonary fibrosis, perimuscular fibrosis, Symmers"" fibrosis, pericentral fibrosis, hepatitis, dermatofibroma, binary cirrhosis, alcoholic cirrhosis, acute pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, kidney fibrosis/glomerulonephritis, kidney fibrosis/diabetic nephropathy, scleroderma/systemic, scleroderma/local, keloids, hypertrophic scars, severe joint adhesions/arthritis, myelofibrosis, corneal scarring, cystic fibrosis, muscular dystrophy (duchenne""s), cardiac fibrosis, muscular fibrosis/retinal separation, esophageal stricture, payronles disease. Further, fibrotic disorders may be induced or initiated by surgery such as scar revision/plastic surgeries, glaucoma, cataract fibrosis, corneal scarring, joint adhesions, graft vs. host disease, tendon surgery, nerve entrapment, dupuytren""s contracture, OB/GYN adhesions/fibrosis, pelvic adhesions, peridural fibrosis, restenosis. Still further fibrotic disorders may be induced by chemotherapy, including, for example lung fibrosis and the like.
The compounds described herein, or pharmaceutically acceptable addition salts or hydrates thereof, can be delivered to a subject, including a human, using a wide variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, subcutaneous and intravenous injections.
The compounds described herein, or pharmaceutically acceptable salts and/or hydrates thereof, may be administered singly, in combination with other compounds of the invention, and/or in cocktails combined with other therapeutic agents. Of course, the choice of therapeutic agents that can be co-administered with the compounds of the invention will depend, in part, on the condition being treated.
For example, the compounds of the invention can be administered in cocktails containing agents used to treat the pain and other symptoms and side effects commonly associated with fibrotic disorders. The compounds can also be administered in cocktails containing other agents that are commonly used to treat fibrotic disorders.
The active compound(s) may be administered per se or in the form of a pharmaceutical composition containing the active compound(s) and one or more pharmaceutically acceptable carriers, excipients or diluents. Administered compounds may be enantiomerically pure, or may be mixtures of enantiomers. Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks""s solution, Ringer""s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations previously described, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (for example subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
5.5.1 Effective Dosage
Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in cell culture (i.e., the concentration of the test compound which achieves a half-maximal inhibition of the C-proteinase activity). Such information can be used to more accurately determine useful doses in humans.
A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient""s condition. See, e.g., Fingl et al., 1975, in xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d, Ch. 1 p. 1.
Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the C-proteinase inhibiting effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data; for example, the concentration necessary to achieve 50-90% inhibition of the C-proteinase using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
The amount of composition administered will, of course, be dependent on the subject being treated, on the subject""s weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
5.5.2 Packaging
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of arthritis or any other fibrotic disorder.